A team of researchers from the Istituto Superiore di Sanità (ISS), the Institute of Translational Pharmacology of the National Research Council (Cnr-Ift) and the IRCCS San Raffaele in Rome has recently discovered a new molecular mechanism underlying the loss of memory and cognitive capabilities typical of dementia.
In particular, researchers have identified a protein which plays a crucial role in repairing damage to the DNA double-strand breaks caused by stress and other stimuli within neurons. This discovery is a major step in the early diagnosis of Alzheimer’s Disease, a condition that, based to the most recent ISS data, affects approximately 2 million people in Italy, especially elderly patients.
The study, published in EMBO Reports, shows for the first time that enzyme DNA-PKcs, a protein kinase involved in DNA repair within nervous cells, is also localised in synapses, where transmission of information among neurons occurs. Researchers showed that DNA-PKcs is responsible for the phosphorylation of PSD-95, a key protein in the organization and functioning of synapses. Phosphorylation is a process that modifies the structure of a protein by attaching a phosphate group, thus affecting its function.
Back in 2016, the same research team had discovered that DNA-PKcs activity is inhibited by beta-amyloid, the protein that accumulates in the brain of patients with Alzheimer’s Disease. Failure to repair DNA damage caused by the inhibition of DNA-PKcs contributes to neuron death observed in neurodegenerative diseases, including Alzheimer’s Disease. In fact, a decrease in DNA-PKcs levels and activity has been observed in the brains of patients with Alzheimer’s Disease.
This new study suggests that, both in Alzheimer’s Diseases and other conditions, the reduced activity of enzyme DNA-PKcs, due to accumulation of beta-amyloid, results in decreased levels of PSD-95 in synapses due to lack of phosphorylation. This leads to a synaptic dysfunction, which underlies loss of memory. Lack of PSD-95 phosphorylation could therefore become a new biomarker useful in early diagnosis and monitoring of neurodegenerative diseases caused by cognitive impairment over time.
